The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme

The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme Full article

Journal

International Journal of Molecular Sciences
ISSN: 1661-6596

Output data

Year: 2020, Volume: 21, Number: 19, Article number : 7162, Pages count : 16 DOI: 10.3390/ijms21197162

Tags

Berberine; Cancer; DNA repair enzyme; Molecular modeling; SAR; Tdp1 inhibitor; Tetrahydroberberine

Authors

Gladkova E.D. ^1,2 , Nechepurenko I.V. ¹ , Bredikhin R.A. ¹ , Chepanova A.A. ³ , Zakharenko A.L. ³ , Luzina O.A. ¹ , Ilina E.S. ³ , Dyrkheeva N.S. ³ , Mamontova E.M. ³ , Anarbaev R.O. ^2,3 , Reynisson J. ⁴ , Volcho K.P. ^1,2 , Salakhutdinov N.F. ^1,2 , Lavrik O.I. ^2,3

Affiliations

1	(Scopus) N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, 9, Akademika Lavrentieva Ave., Novosibirsk, 630090, Russian Federation
2	(Scopus) Novosibirsk State University, Pirogova str. 1, Novosibirsk, 630090, Russian Federation
3	(Scopus) Novosibirsk Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences, 8, Akademika Lavrentieva Ave., Novosibirsk, 630090, Russian Federation
4	(Scopus) School of Pharmacy and Bioengineering, Keele University, Hornbeam Building, Staffordshire, ST5 5BG, United Kingdom

Funding (1)

Российский Научный Фонд

19-13-00040

A series of berberine and tetrahydroberberine sulfonate derivatives were prepared and tested against the tyrosyl-DNA phosphodiesterase 1 (Tdp1) DNA-repair enzyme. The berberine derivatives inhibit the Tdp1 enzyme in the low micromolar range; this is the first reported berberine based Tdp1 inhibitor. A structure–activity relationship analysis revealed the importance of bromine substitution in the 12-position on the tetrahydroberberine scaffold. Furthermore, it was shown that the addition of a sulfonate group containing a polyfluoroaromatic moiety at position 9 leads to increased potency, while most of the derivatives containing an alkyl fragment at the same position were not active. According to the molecular modeling, the bromine atom in position 12 forms a hydrogen bond to histidine 493, a key catalytic residue. The cytotoxic effect of topotecan, a clinically important topoisomerase 1 inhibitor, was doubled in the cervical cancer HeLa cell line by derivatives 11g and 12g; both displayed low toxicity without topotecan. Derivatives 11g and 12g can therefore be used for further development to sensitize the action of clinically relevant Topo1 inhibitors. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Gladkova E.D. , Nechepurenko I.V. , Bredikhin R.A. , Chepanova A.A. , Zakharenko A.L. , Luzina O.A. , Ilina E.S. , Dyrkheeva N.S. , Mamontova E.M. , Anarbaev R.O. , Reynisson J. , Volcho K.P. , Salakhutdinov N.F. , Lavrik O.I.
The first berberine-based inhibitors of tyrosyl-dna phosphodiesterase 1 (Tdp1), an important dna repair enzyme

International Journal of Molecular Sciences. 2020. V.21. N19. 7162 :1-16. DOI: 10.3390/ijms21197162 WOS Scopus РИНЦ

Full text from publisher

Published online:

Sep 28, 2020

Web of science	WOS:000586617400001
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